usp spectral library updates · 13/06/2013 · usp spectral library updates bei ma, m.s. manager,...

USP Spectral Library Updates

Bei Ma, M.S. Manager, International Business Development U.S. Pharmacopeial Convention

The USP Excipients Stakeholder Forum June 7, 2013

USP Mission

To improve the health of people around the world through

Public Standards and related programs that help ensure

the Quality, Safety, and Benefit of Medicines and Foods

Other Information to be Collected … …

• Compound Name • CAS No. • Molecular Formula • Molecular Weight • High Resolution Image • Geographic Location • Packaging Information • Storage Conditions • Bar Code / Serialization • Manufacturer • Lot No. / Batch No. • FDA USP UNII Number (if applicable) • FDA Unique Facility Identifier (if applicable) • … …

USP Spectral Library: Development Process

USP: Independent Standard-Setting Organization – Provide Confidentiality Internationally

USP: Globally Recognized Organization – Globally Recognized in over 140 Countries – Globally Focused with Facilities in Brazil, China, India,

Switzerland and Ethiopia

USP: Internationally Recognized Standards – Total 3000 + Reference Standards – Drug Substances, Drug Products, Excipients, Food

Ingredients, Dietary Supplements, Biologics ……

Why USP Spectral Library?

USP Quality Assurance SEAL – Fully implemented through the entire process

USP SOPs and CoAs – Each data (e.g. spectrum has associated USP CoA and SOP) – Fully traceable

Orthogonal Methodology – Multiple analytical technologies implemented – Instrument platform dependent

Key Attributes – Maintain full history and information of materials

Alternatives to Traditional ID Testing Wizard Approach

Uniqueness & Key Features

USP Spectral Library Pilot

Michael Dotlich - Product R&D Jeff Denault - Global Quality Labs Eli Lilly and Company Bei Ma U.S. Pharmacopeial Convention

Collaboration

Eli Lilly and Company is interested in partnering with the USP in establishing a global spectral library as an alternate means to test pharmaceutical raw materials such as excipients and finished drug products. The collaboration will provide an alternate industry standard for sample identity testing that will reduce the potential for introducing counterfeit or adulterated material into the consumer drug system. Lilly continues to develop, evaluate, and implement standard libraries across its drug network and appreciates the opportunity to participate in the shared learning of both generating and evaluating the spectral library data.

6/13/2013 File name/location

Copyright © 2013 Eli Lilly and Company 16



Instrumentation Raman

Truscan RM FTIR

Agilent Cary 630

NIR NIR was considered: Experimental design requirements limited its evaluation within the pilot time window.



Instrumentation Pros and Cons

NIR FT-IR Raman

Portable / Handheld Chemical Specificity (characteristic

chemical bonds) Limited number of samples required

to begin analysis Electronic Records Direct comparison of reference and

sample Sample preparation can be tedious Sampling for “off-line” analysis Packaging

Portable / Handheld Non-specific chemical response –

strong hydrogen bonding influence No sample preparation Electronic Records Limited sampling Rapid analysis ? Packaging Requires chemometric modeling

and expertise to manage Many samples needed to build

model to account for material variability,

Requires model maintenance to ensure appropriateness for intended use

Not a typical Quality Control technology

Portable / Handheld Chemical specificity (characteristic

chemical bonds) “Wet” samples may be analyzed

directly Limited number of samples required

to begin analysis Direct comparison of reference to

sample Electronic Records Rapid analysis No sample preparation Limited sampling - Analysis

through most packaging materials Not a typical Quality Control

technology

Reference Material 1. Raman – Include single reference scans in library. Reference material is to

be representative of tested material and in most cases highly pure (99%+) raw materials. Materials with low level contaminants can be included; however, important that the testing capability is not diluted (e.g. lactose anhydrous with 5% lactose monohydrate).

2. FTIR – Include multiple standard scans, but must exercise caution to make sure items that require failure, will fail..

3. NIR – Model the options, however, the model must be challenged to show specificity to the material and not of a secondary component such as water in the material. Building models can be time consuming.

4. Materials of lower purity are acceptable provided the standard is consistent with all future samples.

5. Most ID methods will not be designed to capture low level impurities, unless, of course the technology is capable (mass spec, GC, NMR).



Chemical Selectivity SELECTIVITY CHALLENGES

Some materials are too similar to be analyzed by Raman alone.

For povidone and crospovidone, two commonly used pharmaceutical excipients, the Raman spectra are not distinguishable.

This lack of selectivity may be addressed through supplemental testing, e.g., Raman plus solubility test or NIR.



250 500 750 1000 1250 1500 1750 2000 2250 2500wavenumber (cm-1)

CROSPOVIDONE AND POVIDONE REFERENCE SCANS

Pilot Materials



Material Name Compendial

Class CAS No. Supplier 1 Supplier 2 USP RS Rationale

Fluoxetine HCl API 59333-67-4 Eli Lilly Eli Lilly Yes Small molecule API with strong raman

scattering Anhydrous

Lactose Excipient 63-42-3

Kerry Bio-Science

Sigma-Aldrich Yes

Similar materials Lactose

Monohydrate Excipient 5989-81-1

Sigma-Aldrich

Fisher Scientific Yes

Lactose Monohydrate

Excipient 64044-51-5 Foremost

Farms USA Sigma-Aldrich No

Sodium Bicarbonate

Excipient 144-55-8 Avantor Sigma-Aldrich Yes Similar materials Sodium

Carbonate Excipient 497-19-8

Strem Chemicals

Fisher Scientific Yes

Microcrystalline Cellulose

Excipient 7558-79-4 JRS Pharma Sigma-Aldrich Yes Medium Raman Scatterer

Titanium Dioxide

Excipient 1317-70-0 (Anatase)

Sigma-Aldrich

Alfa Aesar No Similar materials of different crystal forms. Titanium

Dioxide Excipient

13463-67-7 (Rutile)

Acros Organics

Strem Chemicals Yes

Talc Excipient 14807-96-6 IMI FABI

LLC Sigma-Aldrich No

Poor raman scatterer – good for FTIR/ NIR

Sample Presentation Reference scan robustness was assessed by testing different sample presentations.

1.Polyethylene bags – Ideal for raman and is consistent with testing warehouse stored bulk materials. Will not work with FTIR and possible option for NIR if polyethylene peaks are not included in the model.

2.Glass Vials (1 dram) – Raman and NIR option if sampling is necessary.

3.Neat – A subset of the USP’s digital reference spectral library. Sample placed 5 mm from nose cone.



Sources of Variability FTIR

Analyst – Sample preparation/ handling (e.g. ATR) Instrument – Four instruments/ analysts to capture instrument variability. Material (i.e. source of sample)

Raman Analyst – Expect little analyst effect (i.e. fixed nose cone). Instrument – Six instruments/analysts to capture instrument variability. Material (i.e. source of sample)



Signature Scan Transferability Good Moderate Poor

O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2 O R1 R2O R1 R2 O R1 R2 O R1 R2R2’

R2’

R2’

Reference Standard Collection

USP Collaborative Testing Model – Testing and results from multiple labs are averaged for final result to characterize the reference standard.



Raman – Test from three labs will be included in library.

Infrared – Reference standard scans from three labs will be averaged for final reference scan.

Amount of RSs: NScan Type: 3 (Neat, Vial, Bag)Total Scans / USP Lab: N*3

USP Lab 1 USP Lab 2 USP Lab 3

3*N Raman Signature Scans



USP Raman Digital Reference Spectra Library – USP RM-DRSL (9*N Raman Signature Scans)

Lilly Lab 1

Lilly Lab 2

Lilly Lab 3

Load USP RM-DRSL Load USP RM-DRSL

USP Lab 1

USP Lab 2

USP Lab 3

USP RM-DRSL

Thermo

LabCognition

USP RM-DRSL (SPC Format)

USP RM-DRSL (SPC Format)

Load into Database

USP HQs

Amount of RSs: NScan Type: 1 (Neat)Replicates: 3Total Scans / USP Lab: N*3

USP Lab 1 USP Lab 2 USP Lab 3

3*N Raw IR Reference Spectra

Lilly Lab 1

Lilly Lab 2

Lilly Lab 3

Load USP IR-DRSL Load USP IR-DRSL

USP Lab 1

USP Lab 2

USP Lab 3

Data Analysis & Validation: LabCognition

USP HQs

USP Raw IR Digital Reference Spectra – USP R-IR-DRS (9*N Raw IR Spectra)

USP IR Digital Reference Spectra Library – USP IR-DRSL (N IR Spectra)

3*N Raw IR Reference Spectra 3*N Raw IR Reference Spectra

RUN ORDER MATERIAL PACKAGING Pos1, Rep1 Pos1, Rep2 Pos2, Rep1 Pos2, Rep2 Pos3, Rep1 Pos3, Rep219 Fluoxetine Hydrochloride neat14 Fluoxetine Hydrochloride vial20 Fluoxetine Hydrochloride bag22 Anhydrous Lactose neat17 Anhydrous Lactose vial21 Anhydrous Lactose bag15 Lactose Monohydrate - 1 neat24 Lactose Monohydrate - 1 vial8 Lactose Monohydrate - 1 bag5 Lactose Monohydrate - 5 neat

27 Lactose Monohydrate - 5 vial26 Lactose Monohydrate - 5 bag23 Sodium Bicarbonate neat30 Sodium Bicarbonate vial16 Sodium Bicarbonate bag1 Sodium Carbonate neat7 Sodium Carbonate vial

11 Sodium Carbonate bag13 Microcrystalline Cellulose neat12 Microcrystalline Cellulose vial4 Microcrystalline Cellulose bag3 Titanium Dioxide - A neat6 Titanium Dioxide - A vial2 Titanium Dioxide - A bag

18 Titanium Dioxide - D neat10 Titanium Dioxide - D vial28 Titanium Dioxide - D bag25 Talc neat9 Talc vial

29 Talc bag

Raman Sample Run (6 Instruments)



FTIR Sample Run (4 Instruments)



RUN ORDER MATERIAL PACKAGING ATR1, Rep1 ATR1, Rep2 ATR2, Rep1 ATR2, Rep2 ATR3, Rep1 ATR3, Rep27 Fluoxetine Hydrochloride neat6 Anhydrous Lactose neat

10 Lactose Monohydrate - 1 neat5 Lactose Monohydrate - 5 neat2 Sodium Bicarbonate neat1 Sodium Carbonate neat8 Microcrystalline Cellulose neat3 Titanium Dioxide - A neat9 Titanium Dioxide - D neat4 Talc neat

Applications of Spectral Library The USP global spectral library will provide a robust standard library for raw materials that will be tested for variability (e.g. vendor, instrument, container) allowing the user to minimize their time developing their own reference library.

Similar to the USP Reference Standards, digital reference standards will offer a consistent spectroscopic approach to testing materials as an alternate method to traditional wet chemistry identification testing.

A general chapter (>1000) guidance on the application and use of a spectral library will provide a standard approach for spectroscopic identity analysis and help expand the current methods of testing. 6/13/2013 File name/location


usp spectral library updates · 13/06/2013 · usp spectral library updates bei ma, m.s. manager,...

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